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      Targeted therapy for rare lung cancers: Status, challenges, and prospects

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          Abstract

          Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating an era of personalized medicine for lung cancer. The rare subset of lung cancers accounts for approximately 10%, each displaying distinct clinical characteristics. Treatments for rare lung cancers are mainly based on evidence from common counterparts, which may lead to unsolid clinical benefits considering intertumoral heterogeneity. The increasing knowledge of molecular profiling of rare lung cancers has made targeting genetic alterations and immune checkpoints a powerful strategy. Additionally, cellular therapy has emerged as a promising way to target tumor cells. In this review, we first discuss the current status of targeted therapy and preclinical models for rare lung cancers, as well as provide mutational profiles by integrating the results of existing cohorts. Finally, we point out the challenges and future directions for developing targeted agents for rare lung cancer.

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          Abstract

          Jianxin Xue and colleagues first briefly described rare lung cancers, then summarized the clinical efficacy of FDA-approved targeted agents. Furthermore, they discussed potential targets, with comprehensive mutational profile provided, and the research model status. They finally highlighted the challenges and prospects in developing targeted therapy for rare lung cancers.

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Cancer statistics, 2022

            Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.
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              Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

              First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
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                Author and article information

                Contributors
                Journal
                Mol Ther
                Mol Ther
                Molecular Therapy
                American Society of Gene & Cell Therapy
                1525-0016
                1525-0024
                05 July 2023
                13 May 2023
                : 31
                : 7
                : 1960-1978
                Affiliations
                [1 ]Division of Thoracic Tumor Multimodality Treatment, Cancer Center, the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
                Author notes
                []Corresponding author: Jianxin Xue, Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. radjianxin@ 123456163.com
                [2]

                These authors contributed equally

                Article
                S1525-0016(23)00263-0
                10.1016/j.ymthe.2023.05.007
                10362419
                37179456
                2de29f91-3994-499a-a3c9-c698cb2a3519
                © 2023 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Review

                Molecular medicine
                lung neoplasm,rare cancers,molecular targeted therapy,immune checkpoint inhibitors,preclinical model

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